This invention relates to the preparation and use of poly(amide-co-anhydrides) and poly(imide-co-anhydrides).
Various types of polymers have been tested for use in forming a biodegradable, biocompatible drug delivery device, including poly(esters), poly(amides), poly(urethanes), poly(orthoesters), poly(acrylonitriles), poly(phosphazenes) and poly(anhydrides). Biodegradable controlled release systems for drugs or other biologically active compounds have an advantage over other controlled release systems in obviating the need to surgically remove the non-biodegradable drug depleted device since the biodegradable device degrades as the biologically active compound is released.
The polymer's erosion characteristics in an aqueous media is of particular importance in choosing a polymer for controlled delivery. When water penetrates a device made of a polymer having water labile bonds, hydrolytic degradation occurs internally, forming channels in the device. Thus, in addition to release of incorporated drug from the exterior of the device through surface erosion, there is also internal erosion and uncontrolled bulk release of the drug through channels formed in the device. Release of drug is more controlled, however, when the rate of hydrolytic degradation on the surface of the polymeric device is much faster than the rate of water penetration into the bulk of the matrix. Accordingly, surface eroding polymers are preferred for applications where continuous release over a controlled period of time is required.
Poly(anhydrides) surface erode in vivo due to hydrolysis, rather than by enzymatic degradation. As a result there are fewer variations in the rate of drug release from individual to individual using a poly(anhydride) controlled delivery device than one which degrades enzymatically. Furthermore, poly(anhydride) degradation products are nonmutagenic, noncytotoxic, and have a low teratogenic potential, as discussed by Leong, K. W., D'Amore, P. D., Marletta, M. and Langer, R., J. Biomed. Mater. Res. 20, 51 (1986). These polymers are soluble in common organic solvents (40% w/v) and have low melting points, generally in the range of 40.degree.-100.degree. C., which facilitates fabrication into controlled delivery devices.
The hydrolytic degradation rates of poly(anhydrides) can be altered several thousandfold by simple changes in the polymer backbone, for example, by choosing the appropriate monomers, as shown by Domb and Langer, J. Poly. Sci., 27, 1 (1987). As described in copending application Ser. No. 080,631 entitled "Polyanhydrides with Improved Hydrolytic Degradation Properties" filed July 31, 1987 by Domb and Langer, poly(anhydrides) with a uniform distribution of alkyl and aromatic residues display zero-order kinetic profiles over various periods of time (days to months), indicating that surface erosion rather than bulk erosion is occurring.
In order to provide even greater control over the rate of release of compound from the device, it would be advantageous if a controlled delivery device could be fabricated from polymers containing the material to be delivered as an integral part of the polymeric matrix, as compared to being encapsulated within the matrix. It would be particularly useful if polymers could be formed from peptides or peptide derivatives, many of which have important biological activity, such as hormones.
Previous attempts to make biodegradable drug delivery devices from synthetic poly(amino acids) have suffered from several problems. One major problem is the antigenicity of polymers containing more than three amino acids, provoking an inflammatory response. Another problem is in device fabrication since poly(amino acids) are insoluble in common organic solvents and have high melting points due to the peptide backbone. Further, these polymers generally absorb significant amounts of water which can be deleterious to incorporated substances within the polymer, and alter degradation and release characteristics. Still another problem is the cost of synthesis of the poly(amino acids). For example, high molecular weight poly(amino acids) are often prepared from N-carboxy-anhydrides which are expensive to synthesize even if they are derived from inexpensive amino acids. Finally, poly(amino acids) are enzymatically, not hydrolytically, degraded in vivo, which can result in variations in the rate of degradation and release from individual to individual, as well as in the same person over time due to the changing nature of the cellular response to these materials.
Several efforts have been made to modify poly(amino acids) to overcome these limitations. Sidman, et al., reported in J. Memb. Sci. 7, 277 (1980), that rods formed from copolymers of L-glutamic acid and gamma-ethyl-L-glutamate degraded slowly in vivo, typically over a period of six months. As reported in J. Am. Chem. Soc. 109, 817 (1987), Kohn and Langer synthesized pseudo poly(amino acids) by polymerizing .alpha.-L-amino acids or dipeptides through non-amide bonds, such as ester and iminocarbonate located on the amino acid side chains, rather than at the amino acid termini. These polymers also degrade slowly.
It is therefore an object of the present invention to prepare biodegradable polymers which are made of biologically active compounds, especially peptides and peptide derivatives, which can be released in vivo with activity, without provoking an inflammatory response.
It is a further object of the present invention to prepare biodegradable polymers which are soluble in common organic solvents and have relatively low melting points.
It is a still further object of the present invention to prepare polymers which degrade by hydrolysis.
It is still another object of the present invention to provide a method of preparation of biodegradable polymers which is relatively inexpensive.
It is yet another object of the present invention to prepare polymers that degrade in vivo at rates suitable for controlled drug delivery.